The overall hypothesis of this proposal is that the tissue plasminogen activator/plasminogen (tPA/plg) fibrinolytic cascade, a proteolytic system which has been implicated in the clearance of amyloid-beta (A-beta) peptide, is an important pathway to investigate for developing possible therapeutic agents against Alzheimer's disease (AD). The abnormal deposition of A-beta in the parenchyma and blood vessels of the brain is a pathological hallmark of AD, the most common cause of dementia and cognitive decline in the aged. Additionally, epidemiological studies indicate that diseases that compromise the circulatory system are risk factors for the development of AD, and imply that AD has a cerebrovascular component. The objectives of this proposal are to investigate the role of the tPA/plg system in the progression of AD-like pathology in transgenic mice overexpressing the amyloid-beta precursor protein (A-betaPP). The tPA/plg system activity is depressed in AD transgenic mice and in individuals with AD, due to the expression of plasminogen activator inhibitor-1 (PAl-l), a protein overexpressed during inflammation, commonly seen in AD. To accomplish this goal, we propose three specific aims. First, we plan to investigate the effects of the loss of tPA, plg, or PAl-1 expression in A-betaPP transgenic mice in a C57/BI6 background. Second, we plan to investigate the role of fibrin deposition in exacerbating the pathology and cerebrovascular dysfunction in AD. Third, we plan to identify new compounds that block the interaction of PAl-1 and tPA, and to test these, along with known PAl-1 inhibitors, for their effects in AD mouse models. These experiments will take advantage of transgenic and knockout mouse lines as in vivo paradigms for the development of possible therapeutic intervention strategies, targeting the tPA/plasmin cascade, against AD progression [unreadable] [unreadable]